NZ260028A

NZ260028A - 4-aryl(alkyl)carbonyl-1-(2-oxobenzoxazolyl- and 2-oxobenzothiazolyl-) piperidine (and piperazine) derivatives; pharmaceutical compositions

Info

Publication number: NZ260028A
Application number: NZ260028A
Authority: NZ
Inventors: Ousmane Diouf; Daniel Lesieur; Patrick Depreux; Beatrice Guardiola-Lemaitre; Daniel-Henri Caignard; Pierre Renard; Gerard Adam
Original assignee: Adir
Priority date: 1993-03-05
Filing date: 1994-03-04
Publication date: 1995-03-28
Also published as: US5534517A; CA2116881A1; EP0613898A1; FR2702214A1; JPH072850A; ZA941541B; US5387586A; FR2702214B1; AU5754794A; AU669962B2

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £60028 ?-3 :.ti i . <+: . I C'^.r: CP.1 P^y^lofp; Co^Q4-\ll«^-Wr^l+w^ ! I8 MAR ,1995. 1.3^.0 -h mm RECEIVED NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION NEW (ARYL(ALKYL)CARBONYL)-HETEROCYCLIC COMPOUNDS, PROCESSES FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. We, ADIR ET COMPAGNIE, a French body corporate, of 1 Rue Carle Herbert, F-92415 Courbevoie, Cedex, France hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 -(followed by page la) The present invention relates to new (aryl(alkyl)carbonyi)-ne:erceyciic compounds, to processes for preparing them and to pharmaceutical compositions containing them. It is known that 5-HT2 serotoninergic receptors are associated with an improvement in schizophrenic conditions. They have also shown beneficial effects in anxiety and depression. Compounds having a good affinity for these 5-HT2 receptors would therefore be useful in the clinical situation for the treatment of these pathologies. The Applicant has discovered new (aryl(alkyl)carbonyl)- heterocyclic compounds which have a high affinity for 5-HT2 receptors, some of these compounds also surprisingly having an analgesic activity. Heterocyclic compounds, described as having an affinity for melatoninergic receptors, are known from the state of the art (Patent Application EP 506539) but these compounds do not have any comparable affinity for 5-HT2 receptors nor do they have any analgesic activity. More particularly, the invention relates to the compounds of formula (I): / \ Ar — (CH2)n — C — B N —A (1) II \ / 0 in which: Ar : represents a phenyl or naphthyl group, Ar being unsubstituted or substituted by one or more radicals chosen from halogen,lower alkyl, lower alkoxy and trifluoromethyl, n : represents 0 or an integer from 1 to 4, / / B : represents a -CH or -N group, and, \ \ A : represents a group of formula (A1) or (A2): -2- r> -■> 0 A -E-N (A1) — E R3-N Y 0 (A2) in which E : represents a linear or branched alkylene chain containing 1 to 6 carbon atoms, Ri : represents a radical chosen from hydrogen, hydroxyl, lower alkyl and lower alkoxy, R2 : represents a radical chosen from hydrogen, lower alkyl and RH r5 10 where E1 has the same definition as E as described above and where Ri) and R5 are chosen, independently from one another, from hydrogen and lower alkyl, or form, together with the nitrogen atom which carries them, a heterocycle chosen from pyrrolidine, piperi-dine, substituted piperidine, morpholine, piperazine and 15 substituted piperazine, R3 : represents a radical chosen from hydrogen and lower alkyl, and X : represents a sulfur or oxygen atom, to their optical isomers, and to their addition salts with a pharmaceutical^ acceptable base or 20 acid, it being understood that, except when otherwise specified, the terms "lower alkyl" and "lower alkoxy" denote linear or branched groups containing 1 to 6 carbon atoms, and the term "substituted" assumed by the "piperidine" and "piperazine" heterocycles means that these heterocycles 25 can be substituted in the 4-position by a radical chosen from lower alkyl, aryl and lower arylalkyl, the term "aryl" denoting a phenyl, naphthyl or pyridyl group which can itself be unsubstituted or substituted by one or more radicals cnosen from halogen, lower alkyl, hydroxyl, lower air:c-:y ar.c trifluoromethyl. Mention may be made, among pharmaceutically acceptable acids which can be used to form an addition salt with the compounds of the invention, by way of examples and in a non-limiting way, of hydrochloric, sulfuric, phosphoric, tartaric, malic, maleic, fumaric, oxalic, methanesulfonic, ethanesulfonic, camphoric and citric acids. Mention may be made, among pharmaceutically acceptable bases which can be used to salify the compounds used according to the invention, by way of examples and in a non-limiting way, of sodium hydroxide, potassium hydroxide, triethylamine, diethylamine, ethanolamine, arginine, lysine and diethanolamine. The invention applies to the process for the preparation of the compounds of formula (I), wherein a compound of formula (II): Ar — (CH2)ti — C — B NH (II) II \_/ 0 in which Ar, n and B are as defined in the formula (I), is reacted with a compound of formula (III/A1): 0 Hal-E-N X (III/A1) or of formula (III/A2): Hal — E (III/A2) R3-N Y x 0 in which E, X, Ri, R2 and R3 are as defined in the formula (I) and Hal represents a halogen atom, in order to obtain the corresponding compound of formula (I). the compounds of formula (I) being, if appropriate: purified according to one or more purification methods chosen from crystallization, chromatography on a silica column, extraction, filtration and passing through cnarcoal or resin, separated, in the pure form or in the form of mixtures, into their optical isomers, and salified with a pharmaceutically acceptable acid or base. The invention also applies to the process for obtaining compounds of formula (I/a): 0 / \ N-E-N Ar — (CH2)n — C — B X II \ / (I/a) 0 in which Ar, n, B, E, X, Ri and R2 are as defined in the formula (I), wherein a compound of formula (IV): -5- /—\ Ar — (CH2)n — C — B N-E—Hal* (IV) II W 0 in which Ar, n. B and E are as defined above and Hal' represents a halogen atom, is reacted with a compound of formula (V): 0 in which X, n: and R2 are as described above, in order to obtain the corresponding compounds of formula (I/a), the compounds of formula (I/a) being, if appropriate: purified according to one or more purification methods chosen from crystallization, chromatography on a silica column, extraction, filtration, and passing through charcoal or resin, separated, in the pure form or in the form of mixtures, into their optical isomers, and salified with a pharmaceutically acceptable acid or base. The starting materials used in the processes described above are either commercially available or easily accessible to those skilled in the art according to processes known from the literature or proposed during the preparation examples described below. Na-N X (V) The compounds of formula (II) are, for example, easily accessible to those skilled in the art by reacting a compound of formula (II/a): / \ CI — C — B N — R6 (I I/a) II \ / 0 in which B is as described in formula (I) and R6 represents a hydrogen atom or a protecting group of the nitrogen, with a compound of formula (Il/b): Ar (Il/b) in which Ar is as defined in the formula (I), or with a compound of formula (II/c): Ar-(CH2)n-MgBr (II/c) in which Ar and n are as defined in the formula (I), in order to obtain, if appropriate after removal of the protecting group R0, the corresponding compounds of formula (II). The compounds of formula (IV) are also easily obtained by reacting a compound of formula (II): /—\ Ar — (CH2)n — C — B NH II W 0 (II) in which Ar, n and B are as defined in the formula (I), with an alcohol of formula (VI): Hal'-E-OH (VI) in which E is as defined in the formula (I) and Hal' represents a halogen atom, in order to obtain the corresponding compound of formula (IV). The compounds of formula (III/A1) and (III/A2) are easily access:::.e :o those skilled in the art according to processes analogous to those described in Application EP 506539. The Applicant has discovered that the compounds of the invention had a remarkable affinity for 5-HT2 serotoninergic receptors. This very significant binding ability is revealed in Example A of the present document (Example A: Measurement of the affinity for serotoninergic receptors). This high affinity for 5-HT2 receptors shown by the compounds of the invention turns out to be surprising since the compounds of the prior art mentioned in Application EP 506539 do not in the least show such an affinity for these receptors. The antipsychotic activity of the compounds of the invention was shown by the test of antagonism of amphetamine-induced hyperactivity (Example B of the present application: Study of antagonism of amphetamine- induced hyperactivity). The compounds of the invention also have an anxiolytic activity (Example C: Light-dark cage test). The equally surprising analgesic activity of the compounds of the invention is shown in Example D (hotplate test). The compounds of the invention, by their method of action, are therefore new candidates for the treatment and prevention of pathologies which require psychotropic agents, and the treatment of conditions involving pain. The compounds of the invention are more particularly useful in the treatment and prevention of anxiety, depression and depressive syndromes, psychotic conditions and Parkinson's disease and the treatment of pain. Another subject of the present invention is pharmaceutical compositions containing, as active principle, one or more compounds of formula (I), or -8- their additior. salts with a pharmaceutically acceptable acid or oas-^. combination with one or more pharmaceutically acceptable excipier.ts, vehicles or diluents. Mention can be made, among pharmaceutical compositions according to the invention, by way of examples and in a non-limiting way, of those which are suitable for oral, parental, nasal, rectal, perlingual, ocular or pulmonary administration and especially injectable preparations, aerosols, eye- or nosedrops, simple, film-coated or sugar-coated tablets, capsules, including gelatin capsules, suppositories, creams, ointments and dermal gels. The useful dose varies according to the age and weight of the patient, the administration route, the nature of the ailment and possible associated treatments and ranges between 0.05 mg and 50 mg per 24 hours taken once or twice. STAGE A : 1-(2-CHLOROETHYL)-4-(4-FLUOROBENZOYL)PIPERIDINE 1-acetylpiperidine-4-carboxylic acid 1-Acetylpiperidine-4-carboxylic acid is prepared by bringing a solution of piperidine-4-carboxylic acid in acetic anhydride to reflux for 2 hours and then stirring for 16 hours at room temperature. The solution is then concentrated and the residue is triturated in ether. The solid compound is recovered by filtration. EXAMPLE 1 : 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN- 2-ONE 0 -9- Recrvstallizatior'. solvent : isopropanol/isopropyl ether Melting point : 180-182°C 1-acetyl-ii-(4-fluorobenzoyl)piperidine 1-Acetylpiperidine-4-carboxylic acid is poured into a thionyl chloride solution. The acyl chloride formed precipitates from solution. The solid is dried after washing several times with petroleum ether. The infrared spectrum shows complete conversion of the acid to the acyl chloride. The acyl chloride is slowly added to aluminum chloride in solution in fluorobenzene, with stirring. The mixture is then brought to reflux for 1 hour. The mixture is poured onto ice and the two resulting phases are separated. The aqueous phase is extracted twice with chloroform and the extracts are added to the fluorobenzene separated previously. The organic solution is cried (Na2S0lj) and filtered. The filtrate is concentrated under reduced pressure and a crystalline white solid is obtained. Melting point : 75-78°C 4-(4-fluorobenzoyl)piperidine A solution of l-acetyl-4-(4-fluorobenzoyl)piperidine in 6N hydrochloric acid is brought to reflux for 2 hours. The solution is cooled and then extracted twice with ether. The aqueous solution is made basic (NaOH) and then extracted with benzene. The extracts are dried (Na2S0u) and filtered. The filtrate is concentrated under reduced pressure and the residual oil is converted to a hydrochloric acid salt. Melting point (hydrochloride) : 222-224°C 1-(2-chloroethy1)-4-(4-fluorobenzoyl)piper idine 0.01 mol of the hydrochloride of 4-(4-fluorobenzoyl)piperidine in an ethanolic sodium hydroxide solution is introduced into a 250 cm3 round-bottomed flask equipped with a water-cooled reflux condenser. The reaction mixture is brought to reflux and 0.012 mol of 2-bromoethanol is added. Reflux is maintained for 2 hours, the mixture is allowed to cool, the inorganic precipitate formed is filtered off and the alcohol is evaporated under reduced pressure. - 10- '"V '/ The residue is :aKer. up in 75 cm3 of anhydrous chloroform, the cooled in an ice bath, 0.04 mol of thionyl chloride is added, a water- cooled reflux condenser is fitted and the reaction is continued for four hours at reflux of the solvent. The mixture is allowed to cool, the chloroform is evaporated and then the residue is taken up in absolute alcohol and brought to boiling point in order to remove the thionyl chloride. The absolute alcohol is evaporated and an anhydrous acetone solution saturated with gaseous hydrochloric acid is added to the residue. The precipitate obtained is filtered off and then recrystallized. Melting point (hydrochloride) : 110-112°C Yield : 65* Recrvstallizatior, solvent : anhydrous acetone Elemental analysis : Calculated : C% 52.27 Found : c% 52.68 Infrared spectrometry : 3000-2600 cm-1 v CH (alkyls) 1670 cm-1 v CO 1610-1580 cm-1 v C=C (aromatics) STAGE B: 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN- 2-ONE 0.01 mol of benzothiazolin-2-one is dissolved in dimethylformamide in a 250 cm3 ground-neck flask equipped with a water-cooled reflux condenser. 0.06 mol of potassium carbonate is added and the mixture is brought to reflux. The mixture is left stirring for 30 minutes and 0.012 mol of the hydrochloride of 1-(2-chloroethyl)- 4-(4-fluorobenzoyl)piperidine, dissolved beforehand in dimethyiformamide, is added. Stirring is continued for one hour, the mixture is allowed to cool, the inorganic insoluble material is filtered off and the filtrate is poured onto crushed ice. The precipitate obtained is filtered off, dried, dissolved in anhydrous acetone and then the hydrochloride is precipitated by sparging with a Ht 6.14 Nf 4.38 H% 6.18 Nf 4.41 -11- 2 6 ' stream of dry gaseous hydrochloric acic. The product obtained is f:l off, dried and then recrystallized. Melting point (hydrochloride) : 254-256°C Yield : 67? Recrvstallization solvent : anhydrous acetone Basic nitrogen assay : for one basic nitrogen Basic nitrogen percentage, theory : 3.33* Basic nitrogen percentage, found : 3-61% Elemental analysis : (title compound 7/2 H2O) Calculated : CX 52.18 H% 5.16 N% 5.95 Found : C% 52.11 Hit 5.55 N% 5.78 Infrared spectrometry : 3100-2800 cm-1 V CH (alkyls) 2700-2300 cm-1 v NH+ 1610 cm-1 v CO (NCOS + ketones) 1580 cm-1 •. C=C EXAMPLE 2 : 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{4-[4-(3 TRIPLUOROMETHYLPHENYL )PI PERAZINYL) BUTYL} BENZOTHIAZOLIN-2-ONE The title compound is obtained by carrying out the reaction as in Exampi 1 but replacing benzothiazolin-2-one with the dihydrochloride of 6-{4-[H (3-trifluoromethylphenyl)piperaziny1]butyl}benzothiazolin-2-one. Melting point (trihydrochloride) : 250-252°C Yield : 37? Recrvstallization solvent : absolute alcohol Basic nitrogen assay : for three basic nitrogens Basic nitrogen percentage, theory : 5.39% Basic nitrogen percentage, found : 5.31% Infrared spectrometry : 3080-2840 cm-1 V CH (alkyls) 2500-2000 cm-1 v NH+ 1670 cm-1 v CO (NCOS ♦ ketones) 1580 cm-1 v C=C (aromatics) - 12- f EXAMPLE 3: 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{4-[4-(2-METHOXY-PHENYL) PI PERAZIMYL]BUTYL}BENZ0THIAZ0LIN-2-0NE The title compound is obtained by carrying out the reaction as in Example 1 but replacing benzothiazolin-2-one with the dihydrochloride of 6-{4-[4-(2-methoxyphenyl)piperazinyl]butyl}benzothiazolin-2-one. Melting point (trihydrochloride) : 252-254°C Yield : 30* Recrvstallization solvent : absolute alcohol Basic nitrogen assay : for three basic nitrogens Basic nitrogen percentage, theory : 5.67% Basic nitrogen percentage, found : 5.86% Elemental analysis : (title compound + 3H2O) Calculated : C% 51.60 H% 5.15 N% 6.97 Found : CS 51.93 H% 5.37 N% 6.73 Infrared spectrometry : 3100-2800 cm-1 v CH (alkyls) 2700-2300 cm-1 v nh+ 1670 cra-1 v CO (NCOS ♦ ketone) 1590 cm-1 v C=C (aromatics) 1020 cm-1 v 0CH3 EXAMPLE 4: 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-(4-MORPHO-LIN0BUTYL ) BENZOTHIAZOLIN-2 -ONE 0 ^ A C —< N— CH2 — CH2 — N S II 0 O CH2CH2CH2-CH2-N The title compounc ;s obtained by carrying out the reaction as Example 1 but replacing benzothiazolin-2- one with the dihydrochloride of 6-(4-morpholinobuty1)benzothiazolin-2-one. Melting point (dihydrochloride) : 258-260°C EXAMPLES 5 TO 22: By carrying out the reaction as in Example 1 but replacing benzothiazolin- 2-one in Stage B with: 6-(2-morpholinoethyl)benzothiazolin-2-one, there is obtained: EXAMPLE 5 : 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-(2-MORPHO-LIN0ETHYL)BENZ0THIAZ0LIN-2-0NE 6-[2-(4-phenylpiperazinyl )ethyi ]benzothiazolin-2- one, there is obtained: EXAMPLE 6 : 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-[2-(4-PHENYLPIPERAZINYL)ETHYL]BENZOTHIAZOLIN-2-ONE 6-{2-[4-(3-trifluoromethylphenyl)piperazinyl ]ethyl}benzothiazolin-2-one, there is obtained: EXAMPLE 7 : 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{2-[4-(3- TRIFLUOROMETHYLPHENYL)PIPERAZINYL]ETHYL}BENZOTHIAZOLIN-2-ONE 6-(N,N-dipropylaminoethyl)benzothiazolin-2-one, there is obtained: EXAMPLE 8 : 3-[2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-(N,N-DI-P ROPYLAMINOETHYL)BENZOTHIAZOLIN-2-ONE 6-{2-[4-(2,3,4-trimethoxyphenylmethyl)piperazinyl ] ethyl}benzothiazolin-2-one, there is obtained: EXAMPLE 9 : 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{2-[4-(2,3,4-TRIMETHOXY PHENYLMETHYL)PIPERAZIMYL]ETHYL}BENZOTHIAZOLIN-2-ONE 6-methoxybenzothiazolin-2-one, there is obtained: EXAMPLE 10 : 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-METHOXYBENZOTHIAZOLIN-2-ONE 6-hydroxybenzothiazolin-2-one, there is obtained: EXAMPLE 11 : 3-{2- [ 4-(4-FLUOROBENZOYL) PI PERI DINO ] ETHYL)-6-HYDROXYBENZOTHIAZ0LIN-2-0NE 5-methoxybenzothiazolin-2-one, there is obtained: EXAMPLE 12: 3-{2-[ 4-(4-FLUOROBENZOYL) PI PERIDINO ] ETHYL}-5-METHOXYBENZOTHIAZ0LIN-2-0NE Melting point : 248-250°C 6-(N,N-dipropyiaminoethyl)-5-methoxybenzothiazolin- 2-one, there is obtained: EXAMPLE 13: 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-(N,N-DIPROPYLAMINOETHYL)-5-METHOXYBENZOTHIAZOLIN-2-ONE 6-{2-[4-(3-pyridyl)piperazinyl]ethyl}benzothiazolin- 2-one, there is obtained: EXAMPLE 14: 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{2-[4-(3-PYRIDYL)PIPERAZINYL]ETHYL}BENZ0THIAZ0LIN-2-0NE 6-{4-[4-(2-methylphenyl)piperazinyl]butyl}benzothiazolin-2-one, there is obtained: EXAMPLE 15: 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{4-[4-(2-METHYLPHENYL) PIPERAZINYL ] BUTYL JBENZOTHI AZOLIN-2-0NE 5-methoxy-6-(4-morpholinobutyl)benzothiazolin-2-one, there is obtained: EXAMPLE 16: 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-5-METHOXY-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE 6-[4-(4-naphtnyipiperazinyl)butyl]benzothiazolin-2- one, there obtained: EXAMPLE 17: 3-{2-I4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-[4-(4-NAPHTHYLPIPERAZINYL)BUTYLJBENZOTHIAZ0LIN-2-0NE 6-{4-[4-(Ji-methoxynaphthyl)piperazinyl ] butyl }benzothiazolin-2-one, there is obtained: EXAMPLE 18: 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{4-[4-(4-METHOXYNAPHTHYL)PIPERAZINYL]BUTYL}BENZOTHIAZ0LIN-2-0NE 6-{2-[4-(2-methoxyphenyl )piperazinyl ] ethyl }benzothiazolin-2-one, there is obtained: EXAMPLE 19: 3 —{2 —[4-(4-FLUOROBENZOYL)PIPERIDINOjETHYL}-6-{2-[4-(2-METHOXYPHENYL)PIPERAZINYL]ETHYL}BENZOTHIAZOLIN-2-0NE 6-[2-(4-phenylpiperidino)ethyl]benzothiazolin-2-one, there is obtained: EXAMPLE 20: 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-[2-(4-PHENYLPIPERIDINO)ETHYL]BENZOTHIAZOLIN-2-0NE 6-[3-(4-phenylpiperazin-1-yl)propyl]benzothiazolin- 2-one, there is obtained: EXAMPLE 21: 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-[3-(4-PHENYLPI PER AZ I NYL) PROP YL ]BENZOTHIAZOLIN-2-ONE 6-[4-(4-phenylpiperazin-1-yl)butyl]benzothiazolin-2- one, there is obtained: EXAMPLE 22: 3-{2-[4-(4~FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-[4-(4-PHENYLPIPERAZINYL)BUTYLJBENZOTHIAZ0LIN-2-0NE EXAMPLE 23: 3-{2-[ 4-( 3,4-DIMETH0XYBENZ0YL) PIPERI DINO] ETHYL}BENZOTHI AZOL IN-2-ONE The title compounc is obtained by carrying out the reaction as in Example 1 but starting from 4-(3,4-dimethoxybenzoyl)piperidine in place of 4-(4-fluorobenzoy1)piperidine. EXAMPLE 24: 3-{2-[4-(4-METHOXYBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE The title compound is obtained by carrying out the reaction as in Example 1 but starting from 4-(4-methoxybenzoyl)piperidine in place of 4-(4-fluorobenzoyl)p iperidine. EXAMPLE 25: 3-[2-(4-BENZOYLPIPERIDINO)ETHYL]BENZOTHIAZ0LIN-2-0NE The title compound is obtained by carrying out the reaction as in Example 1 but starting from 4-benzoylpiperidine in place of 4-(4-f luorobenzoy Dpiperidine. EXAMPLES 26 AND 27: The compounds of the following examples are obtained by carrying out the reaction as in Example 1 but using the appropriately substituted piperidines in place of 4-(4-fluorobenzoyl)piperidine. EXAMPLE 26: 3-{2-[4-(3»4-DICHLOROBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE EXAMPLE 27: 3-{2-[4-(4-TRI FLUOROMETHYLBENZOYL )PIPERIDINO] ETHYL } BENZOTH I AZOL IN-2-ONE EXAMPLES 28 TO 41: The compounds of the following examples are obtained by carrying out the reaction as in Example 4 but replacing 4-(4-fluorobenzoyl)piper idine with the appropriately substituted piperidines: EXAMPLE 28: 3 - {2-[4-(4-METH0XYBENZ0YL)PIPERIDINO1ETHYL}-6-(4-MORPHO LINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 29: 3-{2-[4-(4-TRIFLUOROMETHYLBENZOYL)PIPERIDIHO]ETHYL}-6-(4 MORPHOLINOBUTYL) BENZOTH I AZOL IN-2-0NE EXAMPLE 30: 3-{2-[4-(3,4-DICHLOROBENZOYL)PIPERIDINO]ETHYL}-6-(4 MORPHOL I NOBUTYL) BENZOTH I AZOL IN-2 -ONE EXAMPLE 31: 3-f2-(4-BENZOYLPIPEKlDINO)ETHYL]-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 32 : 3—{2—[4 — { 3,5-DIBR0M0-2,6-DIMETHOXYBENZOYL)PIPERIDINO]ETHYL}-6-(4 MORPHOLINOBUTYL) BENZOTHI AZOLIN-2-ONE EXAMPLE 33: 3-{2-[4-(4-CHL0R0BENZ0YL)PIPERIDI NO]ETHYL}-6 -(4-MORPHO LINOBUTYL)BENZOTHIAZOLIN-2-0NE EXAMPLE 34: 3-{ 2-[ 4-(3-PHENYLPROPIONYL)PI PERIDINO]ETHYL}-6-(4-M0RPH0 LINOBUTYL) BENZOTHI AZ0LIN-2-0NE EXAMPLE 35: 3-{2-14-(5-PHENYLVALERYL)PIPERIDI NO]ETHYL}-6 -{4-MORPHO LINOBUTYL)BENZOTHIAZ0LIN-2-0NE EXAMPLE 36: 3-{2-{4-[4-(4-FLUOROPHENYL)BUTYRYL]PIPERIDINO}ETHYL]-6-(4 MORPHOLINOBUTYL)BENZOTHI AZOLIN-2-ONE EXAMPLE 37: 3-{3-[4-(4-FLUOROBENZOYL)PIPERIDINO]-2-METHYLPROPYL}-6-(4 MORPHOLINOBUTYL ) BENZOTHI AZ0LIN-2-0NE EXAMPLE 38: 3-{2-[4-(6-FLUORONAPHTHYLCARBONYL)PI PER IDINO J ETHYL} - 6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 39: 3-{2-[4-(NAPHTHYLCARBONYL)PIPERIDINO]ETHYL}-6-(4-MORPHO-LINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 40: 3 - { 2-14-(7-METH0XYNAPHTHYLCARB0NYL)PI PER ID I NO]ETHYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-0NE example 41 : 3 - {4 - [ 4 - (4-FLUOROBENZOYL) PI PER IDINO} BUTYL} -6- (4-MORPHOLINOBUTYL ) BENZO-thIAZOLIN-2-ONE EXAMPLE 42 : 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{3-[4-(2-METHOXYPHENYL)PIPERAZINYL ] -2-METHYLPROPYL}BENZOTHIAZ0LIN-2-0NE The title compound is obtained by carrying out the reaction as in Example 1 but replacing benzothiazol in-2- one with 6-(3-[4-(2-methoxypheny1)piperazinyl]-2-methylpropyl}benzothiazolin-2-one. EXAMPLE 43 : 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYLJBENZOXAZOLIN-2- ONE The title compound is obtained by carrying out the reaction as in Example 1 but replacing benzothiazolin-2- one with benzoxazolin-2-one. EXAMPLE 44 : 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{4-[4-(3-TRIFLUOROMETHYLPHENYL)PIPERAZINYL}BUTYL}BENZOXAZOLIN-2-ONE The title compound is obtained by carrying out the reaction as in Example 1 but replacing 6-{4-[4-(3-trifluoromethylphenyl)piperazinyl]butyl} -19- ' j ' / . -benzothiazolir. 2 - one with 6-{4-[4-(3-trifluoromethylpheny. piperazinyl]butyl}benzoxazolin-2-one. EXAMPLE 45 : 3-{2-[4-(4-FLUOROBENZOYL ) PIPERIDINO]ETHYL}-6-{U-[ 4- ( 2-METHOXYPHENYL) PI PER AZ I NYL ] BUTYL } BENZOXAZOLIN-2-0NE The title compound is obtained by carrying out the reaction as in Example 3 but replacing 6-{4-[4-(2-methoxypheny1)piperazin- 1 -yl]butyl}benzothiazolin-2-one with 6-{4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl}benzoxazolin-2-one. EXAMPLE 46 : 3-{2-[4-(4-FLUOROBENZOYL)PI PERIDINO]ETHYL}-6-(4-MORPHO-LI NOBUTYL ) BENZOX AZOL IN-2-ONE The title compond is obtained by carrying out the reaction as in Example 4 but replacing 6-(^-morpholinobutyl)benzothiazolin-2-one with 6—(4-morpholinobuty1)benzoxazolin-2-one. EXAMPLE 47 : 3- {2- [ 4- (4-FLUOROBENZOYL) PI PERAZI NYL) ETHYL} BENZOTH I AZOL IN-2-0NE The title compound is obtained by carrying out the reaction as in Example 1 but starting, in Stage A, from piperazine- 1-carboxylic acid in place of piperidine-4- carboxylic acid. EXAMPLE 48 : 3-METHYL-6-{2- [ 4- (4-FLUOROBENZOYL) PI PERI DINO ] ETHYL } BENZOTHI AZOL IN-2-0NE S N-CH3 0 -20 - 2 0 stage a : 3-METHYL-6-(2-BROMOETHYL) BENZOTHI AZ0LIN-2-0NE 0.15 mol of 3-methyl-6-broinoacetylbenzothiazolin-2-one (42.9 g) is dissolved in 1 mol of trifluoroacetic acid (77 cra3) in a 250 cm3 ground-neck flask. 0.33 mol of triethylsilane (52.70 cm3) is introduced dropwise using a dropping funnel, with magnetic stirring. A calcium chloride drying tube is fitted ana stirring is maintained for the required time at room temperature. The reaction mixture is poured into 500 cm3 of ice-coid water. The precipitate obtained is filtered off, washed with water until the wash liquors are neutral, dried and then recrystallized. Reaction time : 20 hours Melting point : 97-98°C Yield : 86? Recrvstallization solvent : cyclohexane Elemental analysis : Calculated : C? 44.13 H? 3.70 Found : C? 44.26 H? 3.60 Infrared spectrometry : 3050-2850 cm-1 v CH (alkyls) 1660 cm-1 v CO (NCOS) 1610—1580 cm-1 v q-q (aromatics) STAGE B: 3-METHYL-6-{2-[4-( 4-FLUOROBENZOYL) PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE 0.01 mol of 3-methyl-6-(2-bromoethyl)benzothiazolin-2-one is dissolved in 50 cm3 of anhydrous acetone. The acetone is heated to reflux. 0.022 mol of triethylamine in solution in 20 cm3 of anhydrous acetone is added and then 0.01 mol of the hydrochloride of 4-(4-fluorobenzoyl)piperidine is added with magnetic stirring. Heating is continued for 24 hours and then the triethylamine hydrobromide formed is filtered off. The filtrate is evaporated and the residue is taken up in 50 cm3 of a 1M HC1 solution. The expected product precipitates, is filtered off, is dried and is then recrystallized. N? 5.15 N? 5.34 -21 - Melting point (hydrcen.cride) : 224-226°C Yield : 62? Recrvstallization solvent : absolute alcohol Basic nitrogen assay : for one basic nitrogen Basic nitrogen percentage, theory : 3.22? Basic nitrogen percentage, found : 2.94? Infrared spectrometry : 3000-2800 cm-1 v CH (alkyls) 2600-2400 cm-1 v nh 1660 cm-1 v co (NCOS) 1660 cm~1 v co (ketone) 1600-1530 cm-1 v C=C (aromatics) EXAMPLE 49 : 3-METHYL-6-{4-[4-( 4-FLUOROBENZOYL) PI PERI DINO ]BUTYL}BENZOTHIAZOLIN-2-ONE The title product is obtained by carrying out the reaction as in Example 48 but replacing, in Stage A, 3-methyl-6-bromoacetylbenzothiazolin-2-one with 3-methyl-6-nromobutyrylbenzothiazolin-2-one. EXAMPLES 50 TO 52 : The compounds of the following examples are obtained by carrying out the reaction as in Example 48 but replacing, in Stage B, 4-(4-fluorobenzoyl)piperidine with the appropriately substituted piperidines: EXAMPLE 50 : 3-METHYL-6- { 4- [ 4- (4-CHLOROBENZOYL) PI PER IDI NO ] ETHYL } BENZOTH I AZOL IN-2-0NE EXAMPLE 51 : 3-METHYL-6-[ 4- (4-BENZOYLPI PERI DINO ) ETHYL ] BENZOTHI AZ0LIN-2-0NE EXAMPLE 52 : 3-METHYL-6-{4-[4-(4-METHOXYBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE EXAMPLE 53 : 3-METHYL-6- { 2- [ 4- ( 4-METHOXYBENZOYL ) PI PERI DI NO ] ETHYL JBENZOXAZOLIN-2-ONE -22 - n ^ v L \j The title product :s ootained by carrying out the reaction as in Example 48 but replacing, in Stage A, 3-methyl-6-bronioacetylbenzothiazolin-2-one with 3-methyl-6-bromoacetylbenzoxazolin-2-one. EXAMPLE 54 : 6-{2-[ 4-(4-FLUOROBENZOYL) PIPERIDINO]ETHYL}BENZOTHI AZOLIN-2-ONE The title compound is obtained by carrying out the reaction as in Example 48 but replacing 3-methyl-6-bromoacetylbenzothiazolin-2-one with 6-bromoacetylbenzothiazolin-2-one. EXAMPLE 55 : 6-{4-[4-(4-FLUOROBENZOYL)PIPERIDINO]BUTYL}BENZOTHIAZOLIN-2-ONE The title product is obtained by carrying out the reaction as in Example 48 but replacing, in Stage A, 3-methyl-6-bromoacetylbenzothiazolin-2-one with 6-bromobutyrylber.zothiazolin-2-one. EXAMPLES 56 TO 58 : The compounds of the following examples are obtained by carrying out the reaction as in Example 55 but replacing, in Stage B, 4—(4-fluorobenzoyl)piperidine with the appropriately substituted piperidines: EXAMPLE 56 : 6-{4-[4-(4-CHLOROBENZOYL)PIPERIDI NO ] BUTYL}BENZOTHIAZOLIN-2-ONE EXAMPLE 57 : 6-[4-(4-BENZOYLPIPERIDINO)BUTYL]BENZOTHIAZ0LIN-2-0NE EXAMPLE 58 : 6-{4-[4-( 4-METHOXYBENZOYL ) PI PER IDI NO ] BUTYL} BENZOTH I AZOL IN-2-0NE EXAMPLE 59 : 3-METHYL-6-(4-[ 4-(4-FLUOROBENZOYL) PI PERI DINO ] BUTYL JBENZOXAZOLIN-2-ONE -23- 2 6 r ^ The title product :s octained by carrying out the reaction as in Example 48 but replacing 3-methyl-6-bromoacetylbenzothiazolin-2-one with 3-methyi-6-bromobutyrylbenzoxazolin-2-one. EXAMPLES 60 TO 62 : The compounds of the following examples are obtained by carrying out the reaction as in Example 59 but replacing, in Stage B, 4-(4-fluorobenzoyl)piperidine with the appropriately substituted piperidines: EXAMPLE 60 : 3-METHYL-6- {4 - [ 4- (4 -CHLOROBENZOYL) PI PERI DI NO ] BUTYL ) BENZOX AZOLIN-2-0NE EXAMPLE 61 : 3-METHYL-6-14- (4-BENZOYLPI PERI DI NO) BUTYL ] BENZOXAZOLIN-2-ONE EXAMPLE 62 : 3-METHYL-6-{4- [ 4- (4-METHOXYBENZOYL) PI PER I DI NO ] BUTYL JBENZ0XAZ0LIN-2-0NE EXAMPLE 63 : 6-{4-[4-(4-FLUOROBENZOYL)PIPERIDINO]BUTYL}BENZOXAZOLIN-2-ONE The title product is obtained by carrying out the reaction as in Example 48, but replacing 3-methyl-6-bromoacetylbenzothiazolin-2-one with 6-bromobutyrylbenzoxazolin-2-one. EXAMPLES 64 TO 66 : The compounds of the following examples are obtained by carrying out the reaction as in Example 63 but replacing, in Stage B, 4-(4-fluorobenzoyl)piperidine with the appropriately substituted piperidines: EXAMPLE 64 : 6-{4- [4-( 4-CHLOROBENZOYL) PIPERIDINO ] BUTYL]BENZ0XAZ0LIN-2-0NE EXAMPLE 65 : 6-[4-(4-BENZOYLPIPERIDINO)BUTYL]BENZOXAZOLIN-2-ONE ?4- EXAMPLE 66 : 6- (4- [ 4 - (4-METHOXYBENZOYL) PI PERIDINO] BUTYL} BENZOXAZOLIN-2-ONE EXAMPLE A : MEASUREMENT OF THE AFFINITY FOR SEROTONINERGIC RECEPTORS PROTOCOL: The in-vitro affinity of the compounds of the invention was determined: for 5-HTia serotoninergic receptors, by measuring the displacement of 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), on rat hippocampus preparations, for 5-HTic serotoninergic receptors, by measuring the displacement of N-methylmesulergine, on rat frontal cortex and hippocampus preparations, for 5-HTid serotoninergic receptors, by measuring the displacement of 5-hydroxytryptamine, on rat cortex, striatum and globus pallidus preparations, for 5-HT2 serotoninergic receptors, by measuring the displacement of aminoiodoketanserin, on rat frontal cortex preparations, for 5-HT3 serotoninergic receptors, by measuring the displacement of BRL 436941 on rat area postrema preparations. RESULTS : The compounds of the invention show a very high affinity for 5-HT2 serotoninergic receptors. As examples, the compounds of Examples 1 and 3 have an IC50 (concentration inhibiting binding of the labelled ligand by 50%) of the order of 10-9 m to 10-10 m (compounds of Examples 1 and 3 : IC50 : 10-9 m, compound of Example 4 : 5.10-10 m). The compounds of the invention also show a significant binding selectivity for 5-HT2 receptors with respect to other serotoninergic receptors. The compounds of Application ep 506539 do not in the least show such an affinity and selectivity for 5-HT2 receptors. EXAMPLE B : ANTIPSYCHOTIC ACTIVITY : STUDY OF ANTAGONISM OF AMPHETAMINE-INDUCED HYPERACTIVITY 25 2:3 ~ Tne selective antagonism of amphetamine-induced hyperactivity is regarded as an indicator of an antipsychotic activity. protocol : An injection by the IP route of 2 mg/kg of amphetamine induces a marked measurable hyperactivity. Sprague-Dawley rats weighing 200 to 250 g receive the compounds to be tested by the IP route before administration of the amphetamine and the locomotory activity is then measured 30 minutes later for a period of 30 minutes. 12 animals are tested per dose. Reference: Costall B. et al. - Brain Res., J2^ : 89-111. results : The compounds of the invention very significantly inhibit amphetamine-induced hyperactivity. example c : measurement of anxiolytic activity : light/dark cage test Rats prefer enclosed and dark spaces to open and illuminated spaces. This preference is reflected in the proportion of time spent in enclosed and dark spaces. A characteristic of anxiolytic compounds is to increase the time spent in open and illuminated spaces. protocol : The animals are placed in a cage consisting of 2 compartments, one being open and illuminated and the other being dark and enclosed. The time spent by the animal in each of the compartments, as well as the number of movements from one compartment to the other, is measured for a period of 5 minutes. 10 animals are studied per dose. Reference: Crawley J.N., Pharmacol. Biochem. Behav., 1981, vol 15, p 695-699. results : It clearly appears that the compounds of the invention have an anxiolytic activity since they increase very significantly the time spent by the animals in the illuminated compartment. -26- EXAMPLE D : analgesic activity : hotplate test Rats or mice are placed on a hotplate (58°C) inside a Plexiglas® cylinder. The reaction time which the animal takes to lick its paws is measured. If no reaction is recoraed, the test is terminated after 120 seconds. 10 animals are studied per dose. The tested compound is usually administered i.p. 30 minutes before the test. 16 mg.kg-1 i.p. of morphine is used as the reference compound which inhibits the reaction time which the animais takes to lick its paws by 129?. Reference: Eddy N.B., Liembach D., 1959. Synthetic Analgesics : II-dithienylbutenyl and dithienylbutylamines. J. Pharmacol. Exp. Ther., 107 : 385-393. Results : the compounds of the invention very significantly increase the reaction time which the animal takes to lick its paws. For example, 0.25 mg.kg-1 of the compound of Example 48 inhibited this reaction time by 175?. example e : measurement of the toxicity The toxicity was tested after oral administration of a 650 mg/kg dose to groups of 8 mice (26 ±2 grams). The animals are observed at regular intervals during the first day and daily during the 2 weeks following the treatment. It appears that the compounds of the invention are not toxic at a dose of 650 mg/kg, and no disorder is generally observed after administration of such a dose. example f : pharmaceutical composition Tablet containing a 2.5 mg dose of 3-{2-[4-(4-fluorobenzoyl)piperidino] </div>

Claims

<div class="application article clearfix printTableText" id="claims"> -27- 26- ethyl]-6-(4-morpholincDutyl)benzothiazolin-2-one Preparation for 1000 tablets: 3-{2-[4-(4-Fluorobenzoyl)piperidino]ethyl}-6-(4-morpholinobutyl)benzothia zolin-2-one 2.5 g Wheat starch 15 g Maize starch 15 g Lactose 65 g Magnesium stearate 2 g Silica 1 g Hydroxypropyl cellulose 2 g -28- WHATSAE CUM 8

1. A compound of formula (I): Ar - (CH2)n — C — B N —A (I) \ / 0 in which: Ar : represents a phenyl or naphthyl group, Ar being unsubstituted or substituted by one or more radicals chosen from halogen, lower alkyl, lower alkoxy and trifluoromethyl, n : represents 0 or an integer from 1 to 4, / / B : represents a -CH or -N , group, and \ \ A : represents a group of formula (Al) or (A2): 0 -E-N X 0 (a1) (a2) 29- 2 e c n i i in which: E : represents a linear or branched alkylene chain containing 1 to 6 carbon atoms, Ri : represents a radical chosen from hydrogen, hydroxy1, lower alkyl and 5 lower alkoxy, R2 : represents a radical chosen from hydrogen, lower alkyl and /RH -Ei-N N R5 where Ei has the same definition as E as described above and where Rii and R5 are chosen, independently from one another, from hydrogen and 10 lower alkyl, or form, together with the nitrogen atom which carries them, a heterocycie chosen from pyrrolidine, piperidine, substituted piperidine, morpholine, piperazine and substituted piperazine, R3 : represents a radical chosen from hydrogen and lower alkyl, and X : represents a sulfur or oxygen atom, 15 its optical isomers, and its addition salts with a pharmaceutically acceptable base or acid, it being understood that, except when otherwise specified, the terms "lower alkyl" and "lower alkoxy" denote linear or branched groups containing 1 to 6 carbon atoms, and the term "substituted" assumed by the 20 "piperidine" and "piperazine" heterocycles means that these heterocycles can be substituted in the 4-position by a radical chosen from lower alkyl, aryl and lower aryialkyl, the term "aryl" denoting a phenyl, naphthyl or pyridyl group which can itself be unsubstituted or substituted by one or more radicals chosen from halogen, lower alkyl, hydroxy1, lower alkoxy and 25 trifluoromethyl.

2. The compound as claimed in claim 1, wherein Ar represents a 4-fluorophenyl group, its optical isomers, and its addition salts with a pharmaceutically acceptable base or acid. 30

3. The compound as claimed in claim 1, wherein Ar represents a U-fluorophenyl group, n is equal to zero and 30- / B represents a -CH group, \ its optical isomers, and its addition salts with a pharmaceutically acceptable base or acid.

4. The compound as claimed in claim 1, wherein R2 represents a 4-morpholinobutyl group, its optical isomers, and its addition salts with a pharmaceutically acceptable base or acid.

5. The compound as claimed in claim' 1, which is 3-{2-[4-(4-fluorobenzoyl )piperidino]ethyl}benzothiazolin~=2-one and its addition salts with a pharmaceutically acceptable acid.

6. The compound as claimed in claim 1, which is 3-{2-[4-(4-fluorobenzoyl )piperidino]ethyl} -6-{ U — [U-< 3-tri-fluoromethylphenyl)piperazinyl]butyl}benzothiazolin-2-one and its addition salts with a pharmaceutically acceptable acid.

7. The compound as claimed in claim 1, which is 3-{2-[4-(4-fluorobenzoyl) piper id ino]ethyl}-6-(4-morpholinobutyl) benzothiazol in-2-one and its addition salts with a pharmaceutically acceptable acid.

8. The compound as claimed in claim 1, which is 3-methyl-6-{4-[4-(4-fluorobenzoyl)piperidino]butyl}benzothiazolin-2-one and its addition salts with a pharmaceutically acceptable acid.

9. A process for obtaining the compound of formula (I) as claimed in claim 1, wherein a compound of formula (II): / \ Ar — (CH2)n — C — B NH (II) II \ / 0 -31 - in which Ar, n and B are as defined in the formula (I) as claimed in claim 1, is reacted with a compound of formula (III/A1) or of formula .(III/A2): Hal-E-N X Hal — E R3-n X Y 0 (hi/ad (iii/a2) in which E, X, Ri, R2 and R3 are as defined in the formula (I) as claimed in claim 1 and Hal represents a halogen atom, in order to obtain the corresponding compound of formula (I) as claimed in claim 1, the compound of formula (I) being, if appropriate: purified according to one or more purification methods chosen from crystallization, chromatography on a silica column, extraction, filtration and passing through charcoal or resin, separated, in the pure form or in the form of a mixture, into its optical isomers, and salified with a pharmaceutically acceptable acid or base.

10. A process for obtaining the compound of formula (I/a): -32- 2 C Ar — (CH2)n — C — B N-E-N I! \ / 0 A (I/a) in which Ar, n, B, E, X, Si and f?2 are as defined in the formula (I) as claimed in claim 1, wherein a compound of formula (IV): /\ Ar (C"2^n — C — B N s. — Hal' (IV) II \ / 0 in which Ar, n, B and E are as defined above and Hal* represents a halogen atom, is reacted with a compound of formula (V): 0 A in which X, Ri and R2 are as described above, in order to obtain the corresponding compound of formula (I/a), the compound of formula (I/a) being, if appropriate: purified according to one or more purification methods chosen from crystallization, chromatography on a silica column, extraction, filtration, and passing through charcoal or resin, separated, in the pure form or in the form of a mixture, into its optical isomers, - 33 - and salified with a cr.armaceutically acceptable acid or base.

11. A pharmaceutical composition containing, as active principle, one or more compounds of formula (I) as claimed in claim 1 or their addition salts with a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients, vehicles or diluents.

12. The pharmaceutical composition as claimed in claim 11, which is useful in the treatment and prevention of pathologies which require psychotropic agents.

13. The pharmaceutical composition as claimed in claim 12, which is useful in the treatment and prevention of anxiety, depression and depressive syndromes, psychotic conditions ancTParkinson's disease. 1U. The pharmaceutical corr.Dosition as claimed in claim 11, which is useful for the treatment cf pain.

15. A compound of formula I as defined in any one of claims 1-8 substantially as herein described with reference to any one of examples 1 to 66.

16. A method for the preparation of a compound of formula I as defined in any one of claims 1-8 substantially as herein described with reference to any one of examples 1 to 66. </div>